Tribbles Homolog 1
Trib1 is the member of tribbles family pseudokinases with Trib2 and Trib3 in mammals and is a homolog of Drosophila tribbles (Yokoyama and Nakamura 2011). Tribbles was first discovered as a regulator of string/cdc25 in morphogenesis (Grosshans and Wieschaus 2000). At same time, Mata et al. showed that tribbles induced degradation of string via the proteasome pathway (Mata et al. 2000). As a result of studies by these two groups, overexpression of tribbles was found to suppress cell cycle at G2 by proteasome-mediated degradation of string. Soon after discovery of tribbles in Drosophila, slbo/C/EBP was found to be regulated by tribbles also via proteasome pathway (Rorth et al. 2000). Mammalian homologs of tribbles consist of three closely related genes, Trib1/C8FW/SKIP1, Trib2/C5FW/SKIP2/SINK, and Trib3/NIPK/SKIP3 (Wilkin et al. 1997; Mayumi-Matsuda et al. 1999; Tang et al. 2000).
Structure of TRIB1 Pseudokinase
A putative nuclear localization signal, [K/R]2X2[D/E]X[D/E], is located within the N-terminus (Hegedus et al. 2007). There are two functionally important motifs in the C-terminal region. A hexapeptide motif [A/D]QVVPD that was identified in TRIB3 as an E3 ubiquitin ligase COP1-binding site is also present in TRIB1 as DQIVPE (Qi et al. 2006). The COP1-binding motif is important for tribbles’ core function for degradation of the C/EBP family proteins. Another important motif in the C-terminus is an MEK-binding site (Yokoyama et al. 2010). The details of these two important motifs are discussed in the next section.
Trib1 Acts as an Adaptor Protein
Drosophila tribbles downregulates string and slbo at the protein level. C/EBPα, a mammalian homolog of slbo, is degraded by Trib1 and Trib2 in a proteasome-dependent manner (Keeshan et al. 2006; Dedhia et al. 2010). Conversely, the increase of C/EBPβ protein was detected in Trib1 knockout mice (Yamamoto et al. 2007). Posttranscriptional suppression of C/EBP proteins is important for myeloid cell differentiation, myeloid leukemogenesis, and adipocyte differentiation (Keeshan et al. 2006; Dedhia et al. 2010; Yokoyama et al. 2010; Naiki et al. 2007).